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PhD S. Kemp

Position
Associate Professor
Main activities
Education, Research
Specialisation
Biochemistry
Focus of research

Identical gene mutations should lead to specific phenotypes; however, this simplistic view does not adequately address the widely varying phenotypes that are commonly observed in many inborn errors of metabolism. Indeed, even identical mutations can lead to widely variable clinical phenotypes, which suggests that additional factors modify disease manifestations.

This situation is clearly exemplified by X-linked adrenoleukodystrophy (ALD), which is the most common leukodystrophy, but also one of the most puzzling inborn errors of metabolism of the central nervous system.

All ALD patients have a mutation in a single gene (ABCD1) and accumulate very-long-chain fatty acids (VLCFA). The disease, however, is characterized by a striking and unpredictable variation in clinical outcomes among men, ranging from adrenal insufficiency to rapidly progressive and fatal cerebral demyelination (cerebral ALD). In adulthood, virtually all men, and 80% of women, with ALD develop progressive spinal cord disease (that is, adrenomyeloneuropathy (AMN)). In the absence of a genotype–phenotype correlation, predicting the disease course is impossible, even within individual families.

Treatment options are limited. For boys with early stage cerebral ALD, a bone-marrow transplant may be curative. However, for AMN, which represents 85% of ALD cases (males and females), no disease modifying therapy is available. The major objective of our research is to resolve the role of VLCFA metabolism in the pathogenesis of ALD and use this knowledge for the development of a rationally based therapy for ALD.

 

 

 

Key publications
  • Engelen Marc, Barbier Mathieu, Dijkstra Inge M. E., Schür Remmelt, de Bie Rob M. A., Verhamme Camiel, Dijkgraaf Marcel G. W., Aubourg Patrick A., Wanders Ronald J. A., van Geel Bjorn M., de Visser Marianne, Poll-The Bwee T., Kemp Stephan X-linked adrenoleukodystrophy in women: a cross-sectional cohort study Brain 2014;137 (Part 3):693-706 [PubMed]
  • Kemp Stephan, Huffnagel Irene C., Linthorst Gabor E., Wanders Ronald J., Engelen Marc Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history Nature reviews. Endocrinology 2016;12 (10):606-615 [PubMed]
  • Kemp Stephan, Berger Johannes, Aubourg Patrick X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 2012;1822 (9):1465-1474 [PubMed]
  • Kemp Stephan, Theodoulou Frederica L., Wanders Ronald J. A. Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance British journal of pharmacology 2011;164 (7):1753-1766 [PubMed]
  • van de Beek Malu-Clair, Dijkstra Inge M. E., van Lenthe Henk, Ofman Rob, Goldhaber-Pasillas Dalia, Schauer Nicolas, Schackmann Martin, Engelen-Lee Joo-Yeon, Vaz Frédéric M., Kulik Wim, Wanders Ronald J. A., Engelen Marc, Kemp Stephan C26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man PLoS ONE 2016;11 (4):e0154597 [PubMed]
All Publications
Research programmes

PhD S. Kemp (Lipid metabolism and Neurotoxicity)

Our ALD research focuses on the following questions and objectives:
1) What is the role of VLCFA in the demyelinating process?
2) What is the genetic basis for the different phenotypes in ALD?
3) Which enzymes are important in the synthesis of VLCFA and how are they regulated?,
4) Development of a therapy for ALD, and
5) Provide reliable information on all aspects of ALD via www.adrenoleukodystrophy.info

During the last years we have:
• Developed methods to analyze synthesis VLCFA synthesis using stable-isotope labeled fatty acids and tandem mass spectrometry (Kemp et al., Mol. Genet. Metab. 2005)
• Identified ELOVL1, a key enzyme involved in VLCFA synthesis (Ofman et al., EMBO Mol. Med. 2010).
• Developed screening assay for the identification of compounds that inhibit VLCFA synthesis and/or toxicity.
• Generated a conditional transgenic mouse with an extra copy of the ELOVL1 that can be activated in a tissue specific to induce VLCFA synthesis (van de Beek et al PLoS One. 2016).
• Demonstrated that
CYP4F2 affects phenotypic outcome in adrenoleukodystrophy by modulating the clearance of very long-chain fatty acids (van Engen et al. Biochim Biophys Acta. 2016).
• Identified proteins that modulate VLCFA toxicity.
• Demonstrated that VLCFA can also be degraded via omega-oxidation. This pathway may function as an escape route (Sanders et al, J.Lipid.Res. 2005; J.Biol.Chem. 2006; FASEB J. 2008;
van Engen et al. Biochim Biophys Acta. 2016).
• Conducted a placebo-controlled study with lovastatin in AMN patients to evaluate the effect of lovastatin on VLCFA in plasma and blood cells (Engelen et al. NEJM. 2010).
• Performed a large study to describe the clinical symptoms in women with ALD (Engelen et al Brain 2014).

The main focus for the research in the next years will be on: 1) the investigation of the therapeutic potential of pharmacological inhibition of VLCFA synthesis, 2) resolving the role that VLCFA play in the pathophysiology of ALD, and 3) the identification of new prognostic biomarkers to improve care for patients with ALD, which is particularly relevant now that newborn screening for ALD is being introduced.

 

 

Others
MEng I.M.E. Dijkstra
PhD M. Engelen
BEng R. Ofman

Prof. PhD R.J.A. Wanders (Biochemistry & Enzymology of Metabolic Disorders)

PhD M. Engelen (Translational studies in (peroxisomal) leukodystrophies)

Current research funding
  • SwanBio Therapeutics
  • The GEIE ELA International
  • ZonMw